We plan to study the molecular basis of action of antitumor drugs that act on protein or nucleic acid biosynthesis or function. It is hoped that such studies will provide a rational basis for the discovery and design of clinically useful chemotherapeutic agents in patients with neoplastic disease. We shall continue our work to elucidate the mechanism whereby the antitumor antibiotic pactamycin selectively blocks the initiation of new polypeptide chains in mammalian cells. Such studies will involve the dissection of the early steps in protein synthesis and localization of pactamycin action to its interaction with specific macromolecular components of this system. Neocarzinostatin, a potent protein antibiotic that is currently undergoing clinical testing in patients with cancer, is one of a group of polypeptide antibiotics with molecular weights over 10,000 daltons that have antitumor properties. The mechanism whereby neocarzinostatin blocks tumor cell growth and DNA synthesis, and leads to the nicking of DNA will be studied both in HeLa carcinoma cells grown in culture and in cell-free systems. Similar studies will be udertaken with other members of this group of agents, in particular, with the antibiotic Macromomycin.